Alkyl dipiperazine derivatives of xanthene-9-carboxylic acid



United States Patent 3,526,630 ALKYL DIPIPERAZINE DERIVATIVES 0F XANTHENE-9-CARBOXYLIC ACID Lajos Toldy, Istvan Toth, Jzsef Borsi, and Istvan Polgari, Budapest, Hungary, assignors to Egyesult Gyogyszer-es Tapszergyar, Budapest, Hungary, a firm No Drawing. Continuation-impart of application Ser. No. 560,054, June 24, 1966. This application Apr, 18, 1969, Ser. No. 817,580 Claims priority, application Hungary, July 2, 1965, (20-957 Int. Cl. C07d 51/70 US. Cl. 260268 7 Claims ABSTRACT OF THE DISCLOSURE Xanthenes having the formula wherein R is normal or branched chain butyl, and the nontoxic acid addition salts thereof.

CROSS-REFERENCE TO PRIOR APPLICATION This is a continuation-in-part of our copending application Ser. No. 560,054, filed June 24, 1966, and now abandoned.

SUMMARY OF THE INVENTION This invention relates to new xanthene derivatives and their salts. More particularly, it relates to a group of compounds having the following Formula I 0 013-0 O-N N-GHz-CHz-N N-R wherein R is selected from the group consisting of normal and branched chain butyl, and their nontoxic acid addition salts.

The invention includes all the stereoisomers and stereoisomeric mixtures of the compounds of the Formula I, not only in free base form but also their nontoxic acid salts.

The compounds of the present invention are conveniently prepared by reacting a compound of the Formula II wherein Y is selected from the group consisting of halogen 3,526,639- Patented Sept. 1, 1970 and sulphonyloxy, with a piperazine derivative of the Formula III wherein X is selected from the group consisting of halogen, hydroxyl, alkoxy and azide.

Another embodiment of the invention for preparing the new compounds of the Formula I consists in reacting a compound of the Formula VI 0 011-0 ON NH with a compound of the Formula VII Y-OHz-CH2-N NR (VII) wherein R and Y have the same meanings as above.

The new compounds of the Formula I possess basic properties and form acid salts upon reaction with inorganic and organic acids, such as hydrochloric, hydrobromic, maleic, fumaric, ethanesulphonic, l,1'-methylene bis (2 naphthol 3 carboxylic), sulphuric, phosphoric, acetic, citric and other pharmaceutically acceptable acids.

The above-described reactions for producing the new compounds of the present invention are conveniently carried out without or with an inert solvent, preferably in the presence of an acid-binding agent.

The compounds of this invention possess valuable pharmacological properties. Thus, the present compounds are useful antiulcer agents. This activity is demonstrated by their inhibition of ulceration in rats. Moreover, they show an anticholinergic activity.

In the following table the activity of the compounds according to the invention to inhibit the ulcerous state as caused by restrain, insulin, reserpine and the method of Shay, that is, by ligating the pylorus, is compared to the activity of the known compound methantheline bromide (,8 diethylaminoethyl 9 xanthene carboxylate methobromide). On the basis of this comparison it can be stated that the compounds according to the invention are considerably less toxic and show very good resorption from the gastro-intestinal tract. The excellent antiulcer effect of these compounds can probably be explained by the fact that in contradistinction to the quaternary compounds previously used in these therapies, the compounds according to the invention cross the blood serum barrier and act on the brain where, due to their central anticholinergic activity, they modify the activity of the vegetative centers. Thus, the therapeutical value of the compounds according to the invention consists mainly in that, by virtue of their central and peripheral anticholinergic elfect, they inhibit the ulcerous gastric state. Electroencephalographic experiments performed on rabbits with the compounds according to the invention have shown that changes in the electric potential of the brain as produced with physostigmine could be readily inhibited with these compounds, while methantheline bromide showed no such effect, using the quantities conventional for such compounds, e.g., 10 mg./kg.

The 1 (xanthene 9' carbonyl) 4 ,8 [4" isobutyl) piperazinyl 1] ethyl piperazine inhibits in dogs the secretion of gastric acid as caused by Gastrine.

chloride in 80 ml. of dry dichloroethane is dropped to the above-mentioned solution. After standing for a night, the separated ttiethyl-amine chlorohydrate is filtered. The filtrate is shaken with aqueous sodium hydrogen carbonate solution and then with water, and the dichloroethane is evaporated. The residue is dissolved in a 1:1 mixture of abs. benzene and abs. ether, whereafter the l-(xanthene- 9' carbonyl) 4 (f3 oxyethyl) piperazine chlorohydrate is precipitated with abs. ethanol containing hydrochloric acid. This product melts, after recrystallization from abs. methanol, at 245247 C.

41.5 g. of this oxyethyl compound is mixed with chloroform and a 10% aqueous potassium carbonate solution, whereafter the chloroformic layer is dried over sodium sulphate and evaporated. The residue is dissolved in dry chloroform, and while boiling and stirring the solution of 11.5 ml. of thionyl chloride in ml. of dry chloroform is added during 1 /2 hours. After boiling for further 3 TABLE.--ANTIULCER ACTIVITY AND TOXICITY OF THE COMPOUNDS ACCORDING TO THE INVENTION AS COMPARED TO THAT OF METHANTHELINE BROMIDE Name of the compounds Restrain Insulin Reserpine Shay I.v. P.o. LDso D.o./i.v.

1-(xanthene-9'-carb0nyl)-4-,6-[4-(n-butyl)-piperazinyl1]-ethyl-piperazine hydrochloride 12. 8 10. 5 19. 0 19. 0 65. 0 596 9. 2 1-(xanthene-9-carbonyl)-4-,B-[4-(isobutyl)-piperazinyl-l]ethyl-piperazine hydrocholride 9. 6 7. 0 6. U 8.0 68. 0 490 7. 2 1-(xantheue9-carb0nyl)-4-;3-[4-(sec. isobutyD- ipcrazinyl-1]-ethyl-piperazine hydrochloride 23. 0 3.8 10. 5 7. 0 76. 0 1, 100 14. 4 Methantheline bromide 20. 7 11. 5 15. 2 3. 4 320 95. 6

I.v.Intravcnous1y, p.o.per 0s.

As indicated above, the products of the invention occur in both the free base and acid salt forms. In some instances it can be desirable to obtain the acid salt or the quaternary derivative from the free base. In this case, the salt can be prepared by reacting the free base with the corresponding acid, preferably in the presence of a suitable solvent permitting isolation of the salt.

On the other hand, in those instances where it is desired to convert the acid salt to the base, this can be ac complished by dissolving the salt in a suitable solvent, neutralizing the solution with a basic material, such as sodium hydroxide and the like, and isolating the desired base by extraction or other suitable means.

The invention is further illustrated by the aid of the following examples which are given for the purpose of illustration only and are not to be construed as limit of invention in spirit or in scope.

EXAMPLE 1 12.1 g. of 1 (xanthene 9' carbonyl) 4 (5 chloroethyl) piperazine are stirred with 14.2 g. of N (n butyl)- piperazine at 135 C. for 3 hours. The cooled reaction mixture is treated with a 10% aqueous sodium carbonate solution, thereafter it is decanted and then washed with water by decantation. The residue is dissolved in chloroform, dried over sodium sulphate and the chloroform distilled ofi under vacuum. The base obtained as residue is dissolved in 120 ml. of abs. ethanol and the l-(xanthene- 9' carbonyl) 4 ,8 [4" (n butyl) piperazinyl 1"]- ethyl-piperazine trichlorohydrate is precipitated with abs. ethanol containing hydrochloric acid. The obtained compound melts, after boiling with abs. methanol, at 278- 280 C., with decomposition.

This compound is mixed with chloroform and a 10% aqueous potassium carbonate solution. The chlorofonmic layer is dried over sodium sulphate and evaporated. The obtained raw base melts, after recrystallizing from acetone, at 104 C.

The 1 (xanthene 9 carbonyl) 4 ([3 chloroethyD- piperazine used as starting compound is prepared in the following way: to a solution of 16.6 g. of N-(fi-oxyethyl)- piperazine in 120 ml. of dry dichloroethane, 23.5 ml. of

triethylamine are added and While cooling and stirring,

the solution of 33.9 g. of xanthene-9'-carboxylic acid hours, about /3 part of the chloroform are distilled off in vacuo, and after giving acetone to the residue, the chlorohydrate of 1-(xanthene-9'-carbonyl)-4-(fl-chloroethyl)-piperazine is precipitated. This product is separated, mixed while cooling with chloroform and aqueous sodium hydrogen carbonate solution, whereafter the chloroformic layer is separated, dried over sodium sulphate, and the chloroform is distilled 0g. The obtained l-(xanthene-9'- carbonyl)-4-(fi-chloroethyl)-piperazine melts, after recrystallization from 7:3 mixture of abs. benzene and petroether, at 127129 C.

EXAMPLE 2 One proceeds as described in Example 1, with the difference, that, instead of N-(n-butyD-piperazine, N-isobutylpiperazine is used. The obtained 1-(xanthene-9'-carbonyl)-4-;8-[4"-(isobutyl-piperazinyl-1"]-ethyl piperazine trichlorohydrate melts, after boiling with abs. methanol, at 278-480 C. with decomposition.

EXAMPLE 3 One proceeds as described in Example 1, with the difference, that, instead of N-(n-butyl)-piperazine, N-(sec. isobutyl)-piperazine is used. The obtained 1(xanthene-9'- carbonyl)-4l9-[4-(sec. isobutyl) piperaziny1-1]-ethyl piperazine trichlorohydrate melts, after boiling with abs. methanol, at 268270 C.

What we claim is:

1. Xanthenes of the formula wherein R is a member selected from the group consisting of normal and branched chain butyl and homogeneous and nontoxic acid addition salts thereof.

2. A xanthene as claimed in claim 1, in which R is n-butyl.

3. Hydrochlorides of the xanthene as claimed in claim References Cited UNITED STATES PATENTS 4.A 1' '1' 1, h'hR' as c m W 18 2,742,472 4/1956 Baltzly et a1 260268 5. Hydrochlorides of the xanthene as claimed in claim 5 3,2629% 7/1966 Cuslc et 260 268 4.

6. A Xanthene as claimed in claim 1, in which R is DONALD D Primary Exammer' sec. isobutyl.

7. Hydrochlorides of the xanthene as claimed in claim 6. 

